The intersection of pharmaceutical and medical device regulation creates one of the most complex areas of EU regulatory compliance. Drug-device combination products, ranging from pre-filled syringes to drug-eluting stents, must satisfy requirements from both regulatory frameworks while maintaining a coherent approach to safety and efficacy.
Article 117 of the Medical Device Regulation (EU) 2017/745 addresses devices used for the administration or removal of medicinal products, establishing requirements that supplement pharmaceutical legislation. Understanding these requirements is essential for manufacturers of both the device and pharmaceutical components.
Understanding the Regulatory Framework
Before examining Article 117 in detail, it is important to understand how the EU regulatory framework categorizes combination products and determines the primary regulatory pathway.
The Principal Mode of Action Principle
EU regulation distinguishes between products based on their principal mode of action (PMOA). If the primary intended effect is achieved through pharmacological, immunological, or metabolic means, the product is regulated as a medicinal product under Directive 2001/83/EC. If the primary effect is achieved through physical or mechanical means, it falls under the MDR.
For many combination products, the medicinal product is the primary component, with the device serving as a delivery or administration mechanism. In these cases, the product is authorized as a medicinal product, but the device component must still meet applicable MDR requirements.
Categories of Combination Products
The regulatory framework recognizes several categories of combination products:
- Integral products: The device and medicinal product form a single integrated unit and are not reusable. Examples include pre-filled syringes and drug-coated balloons.
- Co-packaged products: The device and medicinal product are packaged together but remain separate items. Examples include injection devices packaged with vials of medication.
- Referenced products: The device and medicinal product are marketed separately but one is specifically referenced in the other's labeling. Examples include specific inhalers referenced in a medication's instructions for use.
| Aspect | Integral Products | Co-packaged Products | Referenced Products |
|---|---|---|---|
| Configuration | Single integrated unit | Packaged together, separate items | Marketed separately |
| Examples | Pre-filled syringes, drug-coated balloons | Injection devices with vials | Inhalers referenced in medication IFU |
| Device CE Marking | No separate CE mark | Separate CE mark required | Separate CE mark required |
| Article 117 Applies | Yes | Not directly | Not directly |
| NB Opinion Required | Yes, via competent authority | Standard MDR conformity | Standard MDR conformity |
| Primary Authorization | Medicinal product (EMA/NCA) | Both separately | Both separately |
Article 117 Requirements
Article 117 of the MDR specifically addresses devices intended for the administration of medicinal products. This article creates a bridge between the MDR and pharmaceutical legislation, ensuring that device components of combination products meet appropriate safety and performance standards.
Scope of Article 117
Article 117 applies to devices that are:
- Intended to administer a medicinal product
- Placed on the market together with the medicinal product as a single integrated product intended exclusively for use in that combination
- Not reusable
For products within this scope, the device component does not bear a separate CE mark. Instead, conformity with relevant MDR General Safety and Performance Requirements (GSPRs) is assessed as part of the medicinal product authorization process.
Notified Body Involvement
A critical aspect of Article 117 is the requirement for Notified Body involvement in assessing device conformity. The competent authority responsible for medicinal product authorization (or EMA for centrally authorized products) must consult a Notified Body designated under the MDR.
The Notified Body provides an opinion on:
- Conformity of the device part with the relevant GSPRs set out in Annex I of the MDR
- Whether the device manufacturer's quality management system covers the device component adequately
This opinion becomes part of the medicinal product marketing authorization dossier and must be considered by the authorizing authority in its benefit-risk assessment.
Documentation Requirements
The documentation requirements for Article 117 products are substantial, requiring coordination between pharmaceutical and device regulatory submissions.
Technical Documentation for the Device Component
Even though the device does not receive a separate CE mark, manufacturers must prepare technical documentation equivalent to that required for standalone devices. This includes:
- Device description and specification: Complete description of the device, its materials, components, and functional characteristics.
- Design and manufacturing information: Design history, verification and validation documentation, and manufacturing process descriptions.
- GSPR compliance: Detailed mapping of how each applicable GSPR is addressed, with supporting evidence.
- Risk management: Full risk management file in accordance with ISO 14971, addressing both standalone device risks and risks arising from the drug-device interaction.
- Biocompatibility: Biological evaluation in accordance with ISO 10993, considering the drug product and any potential interactions.
- Stability and compatibility: Evidence that the device maintains its performance over the product shelf life and is compatible with the medicinal product.
Pharmaceutical Dossier Integration
The device documentation must be integrated into the pharmaceutical Common Technical Document (CTD) structure. Typically, device information is included in:
- Module 3.2.P.7: Container closure system, which includes description and specification of the device component.
- Module 3.2.R: Regional information, which may include the Notified Body opinion.
- Module 5: Clinical documentation, which should address the clinical performance of the complete combination product.
The Consultation Process
The practical implementation of Article 117 involves a consultation process between the medicinal product competent authority and the designated Notified Body. Understanding this process is crucial for timeline planning.
EMA Consultation for Centrally Authorized Products
For medicinal products seeking centralized marketing authorization, EMA has established a formal consultation procedure. Key elements include:
- Early engagement: EMA encourages applicants to engage early, ideally during pre-submission meetings, to discuss the device component and planned Notified Body strategy.
- Notified Body selection: The applicant must select a Notified Body designated for the relevant device category under the MDR.
- Opinion request: EMA formally requests the Notified Body opinion as part of the assessment procedure.
- Timeline integration: The Notified Body assessment is integrated into the overall medicinal product assessment timeline.
National Procedures
For nationally authorized or mutually recognized medicinal products, the consultation process is managed by the relevant national competent authority. Processes may vary between Member States, and manufacturers should engage early with the reference Member State to understand specific requirements.
Special Considerations
Several special situations require particular attention when dealing with Article 117 combination products.
Changes to Authorized Products
When changes are made to the device component of an authorized combination product, manufacturers must assess whether the change triggers a variation to the marketing authorization. Significant device changes may require:
- Updated Notified Body opinion
- Revised stability data
- Updated clinical or human factors data
- Modified labeling and instructions for use
Companion Devices
Some combination products include companion devices that are not integral to the primary drug-device combination but are necessary for proper use. Examples include reconstitution devices or dose-preparation equipment. These companion devices may need separate CE marking under the MDR.
Human Factors Requirements
Both pharmaceutical and device regulations increasingly emphasize human factors and usability. For combination products, usability studies must demonstrate that users can safely and effectively use the complete product, including all device interactions. This requires integrated human factors engineering addressing both the pharmaceutical and device aspects.
Key Takeaways
- Article 117 applies to non-reusable devices integrated with medicinal products where the drug is the primary component.
- Notified Body consultation is mandatory for assessing device component conformity with MDR GSPRs.
- Technical documentation for the device component must be equivalent to standalone device requirements.
- Device documentation must be integrated into the pharmaceutical CTD structure for marketing authorization.
- Early engagement with regulatory authorities and Notified Bodies is essential for timeline management.
Strategic Recommendations
Successfully navigating Article 117 requirements requires strategic planning and coordination. Based on experience with numerous combination product programs, we recommend the following approaches:
Early Planning
Begin regulatory planning for the device component early in development. The Notified Body opinion process can significantly impact overall program timelines, and early engagement allows for identification and resolution of issues before they become critical path items.
Integrated Development
Develop the device component using a quality management system that aligns with both pharmaceutical GMP and ISO 13485 requirements. This integrated approach simplifies compliance demonstration and reduces the risk of gaps being identified during assessment.
Coordinated Documentation
Maintain clear traceability between device technical documentation and pharmaceutical dossier sections. Use consistent terminology and cross-references to facilitate review by both device and pharmaceutical assessors.
Stakeholder Communication
Establish clear communication channels between device and pharmaceutical regulatory teams, quality organizations, and clinical development functions. Regular cross-functional meetings ensure alignment on requirements and timelines.
Conclusion
Article 117 of the MDR creates a structured framework for ensuring that device components of combination products meet appropriate safety and performance standards. While the requirements add complexity to the regulatory pathway, they ultimately serve to protect patients by ensuring that both the pharmaceutical and device aspects of combination products are thoroughly evaluated.
Success in this area requires deep understanding of both regulatory frameworks, careful planning, and effective coordination between stakeholders. For manufacturers entering this space, investing in specialized expertise can significantly improve the efficiency and predictability of the regulatory pathway.